Risk of major congenital heart disease in pregestational maternal diabetes is modified by hemoglobin A1c.

OBJECTIVES: The association between pregestational diabetes mellitus (PDM) and risk of congenital heart disease (CHD) is well recognized; however, the importance of glycemic control and other coexisting risk factors during pregnancy is less clear. We sought to determine the relative risk (RR) of major CHD (mCHD) among offspring from pregnancies complicated by PDM and the effect of first-trimester glycemic control on mCHD risk. METHODS: We determined the incidence of mCHD (requiring surgery within 1 year of birth or resulting in pregnancy termination or fetal demise) among registered births in Alberta, Canada. Linkage of diabetes status, maximum hemoglobin A1c (HbA1c) at < 16 weeks' gestation and other covariates was performed using data from the Alberta Perinatal Health Program registry. Risk of mCHD according to HbA1c was estimated as an adjusted RR (aRR), calculated using log-binomial modeling. RESULTS: Of 1412 cases of mCHD in 594 773 (2.37/1000) births in the study period, mCHD was present in 48/7497 with PDM (6.4/1000; RR, 2.8 (95% CI, 2.1-3.7); P < 0.0001). In the entire cohort, increased maternal age (aRR, 1.03 (95% CI, 1.02-1.04); P < 0.0001) and multiple gestation (aRR, 1.37 (95% CI, 1.1-1.8); P = 0.02) were also associated with mCHD risk, whereas maternal prepregnancy weight > 91 kg was not. The stratified risk for mCHD associated with HbA1c ≤ 6.1%, > 6.1-8.0% and > 8.0% was 4.2/1000, 6.8/1000 and 17.1/1000 PDM/gestational diabetes mellitus births, respectively; the aRR of mCHD associated with PDM and HbA1c > 8.0% was 8.5 (95% CI, 5.0-14.4) compared to those without diabetes and 5.5 (95% CI, 1.6-19.4) compared to PDM with normal HbA1c (≤ 6.1%). CONCLUSIONS: PDM is associated with a RR of 2.8 for mCHD, increasing to 8.5 in those with HbA1c > 8%. These data should facilitate refinement of referral indications for high-risk pregnancy screening. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Intravenous thrombolysis in wake-up stroke: real-world data from the Austrian Stroke Unit Registry.

BACKGROUND AND PURPOSE: Data on real-world experience with intravenous thrombolysis (IV tPA) in wake-up stroke (WUS) are limited. The aim of this study was to examine the efficacy and safety of IV tPA in patients with WUS included in the Austrian Stroke Unit Registry. METHODS: Data from a large nationwide stroke unit registry including initial stroke severity, vascular risk factors, comorbidities, treatment with IV tPA, symptomatic intracerebral haemorrhage (sICH) and functional outcome were extracted and analysed. Patients with WUS were compared with patients with known-onset stroke (KOS) regarding the frequency of IV tPA treatment, neurological improvement (National Institutes of Health Stroke Scale score ≥4), sICH and 3-month functional outcome by modified Rankin Scale score using standard statistical tests. RESULTS: A total of 107 895 stroke patients entered the analysis, including 12 534 with WUS and 91 899 with KOS. Altogether, 904 (7.2%) patients with WUS received IV tPA as compared with 16 694 (18.2%) patients with KOS. Patients with WUS who received IV tPA treatment had twofold higher initial National Institutes of Health Stroke Scale score (median 8 vs. median 4) as compared with patients with KOS. There was no statistical difference in functional outcome by modified Rankin Scale score 0-1 at 3 months between patients with WUS and patients with KOS treated with IV tPA (adjusted odds ratio, 1.08; 95% confidence interval, 0.9-1.31). Also, the rate of sICH did not differ (4.1% vs. 4%, P = 0.852). CONCLUSIONS: In this large non-randomized comparison, the safety and efficacy of IV tPA in patients with WUS in the real-world setting seems to be comparable to patients with KOS.

Familial hypercholesterolaemia in patients with ischaemic stroke or transient ischaemic attack.

BACKGROUND AND PURPOSE: Identification of patients with familial hypercholesterolaemia (FH) is a prerequisite for the appropriate management of their excess cardiovascular risk. It is currently unknown how many patients with acute ischaemic stroke or transient ischaemic attack (TIA) are affected by FH and whether systematic screening for FH is warranted in these patients. METHODS: The prevalence of a clinical diagnosis of FH was estimated in a large representative series of patients with acute ischaemic stroke or TIA (ABCD2 score ≥ 3) using the Dutch Lipid Clinic Network Algorithm (DLCNA; possible FH ≥3, probable/definite FH ≥6). RESULTS: Out of 1054 patients included in the present analysis, 14 had probable/definite FH (1.3%; 95% confidence interval 0.6-2.0) and 107 possible FH (10.2%; 8.4-12.0) corresponding to an overall prevalence of potential FH of 11.5%. Prevalences were even higher in patients with stroke/TIA manifestation before age 55 in men or 60 in women (3.1%, 0.6-5.6; and 13.1%, 8.3-17.9) and those with a prior history of cardiovascular disease (2.6%, 0.9-4.3; and 15.1%, 11.3-18.9). Of note, in two-thirds of our patients with probable/definite and possible FH, stroke or TIA was the initial clinical disease manifestation. CONCLUSIONS: The frequency of potential FH, based on clinical criteria, in patients with acute ischaemic stroke or TIA was 11.5% and that of probable/definite FH (1.3%) was similar to recently reported counts for patients with acute coronary syndrome (1.6%). FH screening using the DLCNA is feasible in clinical routine and should be considered as part of the usual diagnostic work-up.

Slow hopping and spin dephasing of Coulombically bound polaron pairs in an organic semiconductor at room temperature.

Polaron pairs are intermediate electronic states that are integral to the optoelectronic conversion process in organic semiconductors. Here, we report on electrically detected spin echoes arising from direct quantum control of polaron pair spins in an organic light-emitting diode at room temperature. This approach reveals phase coherence on a microsecond time scale, and offers a direct way to probe charge recombination and dissociation processes in organic devices, revealing temperature-independent intermolecular carrier hopping on slow time scales. In addition, the long spin phase coherence time at room temperature is of potential interest for developing quantum-enhanced sensors and information processing systems which operate at room temperature.

Floquet spin states in OLEDs.

Electron and hole spins in organic light-emitting diodes constitute prototypical two-level systems for the exploration of the ultrastrong-drive regime of light-matter interactions. Floquet solutions to the time-dependent Hamiltonian of pairs of electron and hole spins reveal that, under non-perturbative resonant drive, when spin-Rabi frequencies become comparable to the Larmor frequencies, hybrid light-matter states emerge that enable dipole-forbidden multi-quantum transitions at integer and fractional g-factors. To probe these phenomena experimentally, we develop an electrically detected magnetic-resonance experiment supporting oscillating driving fields comparable in amplitude to the static field defining the Zeeman splitting; and an organic semiconductor characterized by minimal local hyperfine fields allowing the non-perturbative light-matter interactions to be resolved. The experimental confirmation of the predicted Floquet states under strong-drive conditions demonstrates the presence of hybrid light-matter spin excitations at room temperature. These dressed states are insensitive to power broadening, display Bloch-Siegert-like shifts, and are suggestive of long spin coherence times, implying potential applicability for quantum sensing.

Hyperfine-field-mediated spin beating in electrostatically bound charge carrier pairs.

Organic semiconductors offer a unique environment to probe the hyperfine coupling of electronic spins to a nuclear spin bath. We explore the interaction of spins in electron-hole pairs in the presence of inhomogeneous hyperfine fields by monitoring the modulation of the current through an organic light emitting diode under coherent spin-resonant excitation. At weak driving fields, only one of the two spins in the pair precesses. As the driving field exceeds the difference in local hyperfine field experienced by electron and hole, both spins precess, leading to pronounced spin beating in the transient Rabi flopping of the current. We use this effect to measure the magnitude and spatial variation in hyperfine field on the scale of single carrier pairs, as required for evaluating models of organic magnetoresistance, improving organic spintronics devices, and illuminating spin decoherence mechanisms.

Spin Rabi flopping in the photocurrent of a polymer light-emitting diode.

Electron spin is fundamental in electrical and optical properties of organic electronic devices. Despite recent interest in spin mixing and spin transport in organic semiconductors, the actual spin coherence times in these materials have remained elusive. Measurements of spin coherence provide impartial insight into spin relaxation mechanisms, which is significant in view of recent models of spin-dependent transport and recombination involving high levels of spin mixing. We demonstrate coherent manipulation of spins in an organic light-emitting diode (OLED), using nanosecond pulsed electrically detected electron spin resonance to drive singlet-triplet spin Rabi oscillations. By measuring the change in photovoltaic response due to spin-dependent recombination, we demonstrate spin control of electronic transport and thus directly observe spin coherence over 0.5 s. This surprisingly slow spin dephasing underlines that spin mixing is not responsible for magnetoresistance in OLEDs. The long coherence times and the spin manipulation demonstrated are crucially important for expanding the impact of organic spintronics.

High-Field Phenomena of Qubits.

Electron and nuclear spins are very promising candidates to serve as quantum bits (qubits) for proposed quantum computers, as the spin degrees of freedom are relatively isolated from their surroundings and can be coherently manipulated, e.g., through pulsed electron paramagnetic resonance (EPR) and nuclear magnetic resonance (NMR). For solid-state spin systems, impurities in crystals based on carbon and silicon in various forms have been suggested as qubits, and very long relaxation rates have been observed in such systems. We have investigated a variety of these systems at high magnetic fields in our multifrequency pulsed EPR/ENDOR (electron nuclear double resonance) spectrometer. A high magnetic field leads to large electron spin polarizations at helium temperatures, giving rise to various phenomena that are of interest with respect to quantum computing. For example, it allows the initialization of both the electron spin as well as hyperfine-coupled nuclear spins in a well-defined state by combining millimeter and radio-frequency radiation. It can increase the T(2) relaxation times by eliminating decoherence due to dipolar interaction and lead to new mechanisms for the coherent electrical readout of electron spins. We will show some examples of these and other effects in Si:P, SiC:N and nitrogen-related centers in diamond.

Bottom-up or top-down: unit cost estimation of tuberculosis diagnostic tests in India.

SETTING: Of 18 sites that participated in an implementation study of the Xpert® MTB/RIF assay in India, we selected five microscopy centres and two reference laboratories. OBJECTIVE: To obtain unit costs of diagnostic tests for tuberculosis (TB) and drug-resistant TB. DESIGN: Laboratories were purposely selected to capture regional variations and different laboratory types. Both bottom-up and the top-down methods were used to estimate unit costs. RESULTS: At the microscopy centres, mean bottom-up unit costs were respectively US$0.83 (range US$0.60-US$1.10) and US$12.29 (US$11.61-US$12.89) for sputum smear microscopy and Xpert. At the reference laboratories, mean unit costs were US$1.69 for the decontamination procedure, US$9.83 for a solid culture, US$11.06 for a liquid culture, US$29.88 for a drug susceptibility test, and US$18.18 for a line-probe assay. Top-down mean unit cost estimates were higher for all tests, and for sputum smear microscopy and Xpert these increased to respectively US$1.51 and US$13.58. The difference between bottom-up and top-down estimates was greatest for tests performed at the reference laboratories. CONCLUSION: These unit costs for TB diagnostics can be used to estimate resource requirements and cost-effectiveness in India, taking into account geographical location, laboratory type and capacity utilisation.

Electrical current through individual pairs of phosphorus donor atoms and silicon dangling bonds.

Nuclear spins of phosphorus [P] donor atoms in crystalline silicon are among the most coherent qubits found in nature. For their utilization in scalable quantum computers, distinct donor electron wavefunctions must be controlled and probed through electrical coupling by application of either highly localized electric fields or spin-selective currents. Due to the strong modulation of the P-donor wavefunction by the silicon lattice, such electrical coupling requires atomic spatial accuracy. Here, the spatially controlled application of electrical current through individual pairs of phosphorus donor electron states in crystalline silicon and silicon dangling bond states at the crystalline silicon (100) surface is demonstrated using a high-resolution scanning probe microscope operated under ultra-high vacuum and at a temperature of 4.3 K. The observed pairs of electron states display qualitatively reproducible current-voltage characteristics with a monotonous increase and intermediate current plateaus.

Market assessment of tuberculosis diagnostics in China in 2012.

OBJECTIVE: To assess the 2012 served available market for tuberculosis (TB) diagnostics in China in the sector served by the China Centre for Disease Control and Prevention (CDC) and the hospital sector in China, including both designated TB hospitals and general hospitals. DESIGN: Test volumes and unit costs were assessed for tuberculin skin tests, interferon-gamma release assays (IGRAs), smear microscopy, serology, cultures, speciation tests, nucleic-acid amplification tests (NAATs), drug susceptibility tests and adenosine-deaminase tests (ADA). Data were obtained from electronic databases (CDC sector) and through surveys (hospital sector), and were estimated for the two sectors and for the country as a whole. Test costs were estimated by staff at China CDC, and using published literature. RESULTS: In 2012, the China CDC and hospital sectors performed a total of 44 million TB diagnostic tests at an overall value of US$294 million. Tests used by the CDC sector were smear microscopy, solid and liquid culture and DST, while the hospital sector also used IGRAs, NAATs, ADA and serology. The hospital sector accounted for 76% of the overall test volume and 94% of the market value. CONCLUSION: China has a very large TB diagnostic market that encompasses a wide range of diagnostic tests, with the majority being performed in Chinese hospitals.

Market assessment of tuberculosis diagnostics in India in 2013.

BACKGROUND: India represents a significant potential market for new tests. We assessed India's market for tuberculosis (TB) diagnostics in 2013. METHODS: Test volumes and unit costs were assessed for tuberculin tests, interferon-gamma release assays, sputum smear microscopy, serology, culture, speciation testing, nucleic-acid amplification tests (i.e., in-house polymerase chain reaction, Xpert(®) MTB/RIF, line-probe assays) and drug susceptibility testing. Data from the public sector were collected from the Revised National TB Control Programme reports. Private sector data were collected through a survey of private laboratories and practitioners. Data were also collected from manufacturers. RESULTS: In 2013, India's public sector performed 19.2 million tests, with a market value of US$22.9 million. The private sector performed 13.6 million tests, with a market value of US$60.4 million when prices charged to the patient were applied. The overall market was US$70.8 million when unit costs from the ingredient approach were used for the 32.8 million TB tests performed in the entire country. Smear microscopy was the most common test performed, accounting for 25% of the overall market value. CONCLUSION: India's estimated market value for TB diagnostics in 2013 was US$70.8 million. These data should be of relevance to test developers, donors and implementers.

Connectivity of diagnostic technologies: improving surveillance and accelerating tuberculosis elimination.

In regard to tuberculosis (TB) and other major global epidemics, the use of new diagnostic tests is increasing dramatically, including in resource-limited countries. Although there has never been as much digital information generated, this data source has not been exploited to its full potential. In this opinion paper, we discuss lessons learned from the global scale-up of these laboratory devices and the pathway to tapping the potential of laboratory-generated information in the field of TB by using connectivity. Responding to the demand for connectivity, innovative third-party players have proposed solutions that have been widely adopted by field users of the Xpert(®) MTB/RIF assay. The experience associated with the utilisation of these systems, which facilitate the monitoring of wide laboratory networks, stressed the need for a more global and comprehensive approach to diagnostic connectivity. In addition to facilitating the reporting of test results, the mobility of digital information allows the sharing of information generated in programme settings. When they become easily accessible, these data can be used to improve patient care, disease surveillance and drug discovery. They should therefore be considered as a public health good. We list several examples of concrete initiatives that should allow data sources to be combined to improve the understanding of the epidemic, support the operational response and, finally, accelerate TB elimination. With the many opportunities that the pooling of data associated with the TB epidemic can provide, pooling of this information at an international level has become an absolute priority.

Assembly and functional expression of murine glutathione reductase cDNA: a sequence missing in expressed sequence tag libraries.

Glutathione reductase (GR) is a chemotherapeutic target. Murine GRcDNA, which contains 85% GC in the 38 codons following the start codon, was assembled from the PCR-amplified exon 1 and a downstream cDNA prior to expression in Escherichia coli as a His(6)-tagged protein. Recombinant GR, an FAD-containing homodimer, corresponds in its enzymic and spectral properties to GR isolated from murine Ehrlich ascites tumor cells. Another cDNA, representing GR with a mitochondrial targeting sequence, yielded two distinct enzymically active expression products.

Expression of cytochromes P450 4F4 and 4F5 in infection and injury models of inflammation.

Lipopolysaccharide (LPS) treatment of rats suppresses CYP 4F4 and 4F5 expression by 50 and 40%, respectively, in a direct fashion occurring in the liver. This contention is borne out by essentially parallel dose-dependent changes observed upon treatment of rat hepatocyte cultures with LPS. An alternate avenue of triggering the inflammatory cascade is traumatic brain injury by controlled cortical impact. Such injury brings about a dramatic change in the expression of CYP 4F4 and 4F5 mRNA which reaches its greatest effect 24 h after impact compared with sham-operated but uninjured controls. At time points after 24 h the expression of both isoforms increases dramatically reaching highest levels at 2 weeks post-injury. These changes in mRNA expression are mirrored by changes in protein expression. The results are consistent with the notion that immediately after injury concentrations of leukotriene and prostaglandin mediators are elevated by decreased CYP 4F concentrations. As time after injury increases those conditions reverse. Increased CYP 4F expression leads to diminished concentrations of leukotriene and prostaglandin mediators and then to recovery and repair.

Detection of mycobacterial lipoarabinomannan with an antigen-capture ELISA in unprocessed urine of Tanzanian patients with suspected tuberculosis.

A direct antigen-capture ELISA based on the detection of mycobacterial lipoarabinomannan (LAM) in unprocessed urine was evaluated for its usefulness in clinical practice. In Tanzania, 231 patients with suspected pulmonary tuberculosis (TB) and 103 healthy volunteers were screened with standard TB tests and with the new LAM-ELISA. Of 132 patients with confirmed pulmonary mycobacterial disease (positive sputum culture), 106 were positive using the LAM-ELISA (sensitivity 80.3%). In comparison, the sensitivity of acid-fast bacilli (AFB) sputum microscopy was 62.1% (82 of 132 confirmed cases). Of the 231 patients, 17 were both culture- and AFB-negative, but had typical radiographic signs of pulmonary mycobacterial infection and did not respond to antibiotic treatment. Of these 17 patients, 13 (76.5%) had positive LAM-ELISA test results. To define the specificity of the assay, urine samples from 103 healthy volunteers were also screened using LAM-ELISA. All but one had an optical density below the cut-off (specificity 99%). Of interest was a significant correlation between level of microscopic density of mycobacteria in sputum and LAM antigen concentration in urine (chi2=8.44). The LAM-ELISA is a field-adapted tool that can improve screening standards in countries with a high incidence of TB.

A prodrug form of a Plasmodium falciparum glutathione reductase inhibitor conjugated with a 4-anilinoquinoline.

Glutathione (GSH), which is known to guard Plasmodium falciparum from oxidative damage, may have an additional protective role by promoting heme catabolism. An elevation of GSH content in parasites leads to increased resistance to chloroquine (CQ), while GSH depletion in resistant P. falciparum strains is expected to restore the sensitivity to CQ. High intracellular GSH levels depend inter alia on the efficient reduction of GSSG by glutathione reductase (GR). On the basis of this hypothesis, we have developed a new strategy for overcoming glutathione-dependent 4-aminoquinoline resistance. To direct both a 4-aminoquinoline and a GR inhibitor to the parasite, double-drugs were designed and synthesized. Quinoline-based alcohols (with known antimalarial activity) were combined with a GR inhibitor via a metabolically labile ester bond to give double-headed prodrugs. The biochemically most active double-drug 7 of this series was then evaluated as a growth inhibitor against six Plasmodium falciparum strains that differed in their degree of resistance to CQ; the ED(50) values for CQ ranged from 14 to 183 nM. While the inhibitory activity of the original 4-aminoquinoline-based alcohol followed that of CQ in these tests, the double-drug exhibited similar efficiency against all strains, the ED(50) being as low as 28 nM. For the ester 7, a dose-dependent decrease in glutathione content and GR activity and an increase in glutathione-S-transferase activity were determined in treated parasites. The drug was subsequently tested for its antimalarial action in vivo using murine malaria models infected with P. berghei. A 178% excess mean survival time was determined for the animals treated with 40 mg/kg 7 for 4 days. No cytotoxicity due to this compound was observed. Work is in progress to extend and validate the strategy outlined here.

Do perchlorate and triflate anions bind to the uranyl cation in an acidic aqueous medium? A combined EXAFS and quantum mechanical investigation.

Structural properties of uranyl cations in acidic aqueous perchlorate and triflate solutions were investigated using uranium LIII -edge extended X-ray absorption fine-structure spectroscopy (EXAFS) in conjunction with quantum mechanical calculations of gas-phase model complexes. EXAFS spectra were measured in aqueous solutions of up to 10 M triflic and 11.5 M perchloric acid, as well as mixtures of perchloric acid and sodium perchlorate. In no case is the perchlorate anion coordinated to UO2(2+). The number of equatorial water molecules bound to UO2(2+) is always about five. In the case of the 10 M CF3SO3H solution, an inner-sphere complexation of the triflate is observed with a U-S radial distance of 3.62 Å. These results are in qualitative agreement with quantum mechanical calculations of model uranyl complexes, according to which the interaction energies of anions follow the order perchlorate

In vitro metabolism of chlorpromazine by cytochromes P450 4F4 and 4F5 and the inhibitory effect of imipramine.

The metabolism of chlorpromazine by expressed recombinant cytochromes P450 4F4 and 4F5 cloned from rat brain was analyzed to characterize the individual activities of the isoforms. Both isoforms metabolized chlorpromazine to both the N-demethylated and the S-oxide products. When isoforms were incubated with chlorpromazine in the presence of increasing concentrations of imipramine, imipramine significantly inhibited both N-demethylation and S-oxidation of chlorpromazine. A dilution of the serum fraction of anti-4F antibody was also found to significantly inhibit both S-oxidation and N-demethylation of chlorpromazine by both 4F4 and 4F5.